03 September 2016

Lecture #17: THERAPEUTIC DRUGS IN OVERDOSE




1.      Salicylates

Medications containing salicylates are Alka–Seltzer, Anacin, Aspirin, Bufferin, Excedrin, and Midol. Salicylates are classified as anti–inflammatory, anti– pyretic analgesics and are used to reduce inflammation, fever and pain.

Initially, salicylate toxicity causes respiratory alkalosis because salicylates stimulate the respiratory center of the CNS, causing hyperapnea, tachypnea. Salicylates also inhibit enzyme in the Kreb cycle, causing pyruvate to be converted to lactic acid. Lipid metabolism is increased, amino acid metabolism is decreased and accumulation of organic acids eventually leads to metabolic acidosis.

Clinical symptoms of salicylate toxicity include tinnitus, hyperapnea, tachypnea, lethargy, vomiting and possibly coma, convulsions, and hyperthermia in severe cases. Severity of the overdose is assessed by arterial blood gas and electrolyte results. Respiratory alkalosis is apparent in the early stages of toxicity and metabolic acidosis with an increased anion gap maybe apparent in later stages.

The determination of salicylates in biological fluid is based on the formation of violet colored complex between ferric ion and phenol.

2.      Acetaminophen

Some common trade names of acetaminophen include Tylenol, Datril, and Anacin–3. It has an analgesic and antipyretic properties. An overdose of this drug causes hepatotoxicity.

Symptoms of toxicity

First 24–48 hours – nausea, vomiting or anorexia, liver necrosis begins with hepatic enzymes, bilirubin and prothrombin time.

3–5 days – symptoms resembling that of viral hepatitis occur.

Acetaminophen, unlike most other drugs does have a specific antidote that is used in severe overdose cases. N–acetylcysteine (mucomyst) effectively reduces the amount of liver necrosis by reducing accumulation of toxic acetaminophen metabolite in the liver. Treatment with N–acetylcysteine must begin within 10 hours after ingestion to be maximally effective.


******  DRUGS OF ABUSE  ******

Classification of drugs of abuse

1.      Depressant or downers

a.      Alcohol
b.      Sedative
c.       Narcotics
d.     Tranquilizers

2.      Stimulant or uppers

a.      Cocaine
b.      Amphetamine
c.       Methampenamine

3.      Hallucinogenics

a.      Phencyclidine
b.      Lysergic Acid Diethylamide (LSD)
c.       Mescaline


******  AMPHETAMINE  ******

Are related chemically and their physiological effects to the biologically active principle of the adrenal medulla, namely epinephrine and adrenalin.

John Abel was the first one to recognize and latter to isolate epinephrine in 1890. In 1920, ephedrine was obtained from the Chinese herb Ma huang (Ephedra vulgaris). Ephedrine has a similar action as ephedrine and its effects last longer than epinephrine. Ephedrine was also used in alleviating the symptoms of asthma.

Since it was difficult to obtain natural supplies of ephedrine, amphetamine was synthesized by Gordon Alleles and George Pines in 1927. Like ephedrine, amphetamine has stimulating effect in the central nervous system. Benzidrine inhaler which is used to reduce nasal decongestion is a form of amphetamine.

Uses of amphetamine in medicine

1.      To keep the patient awake in narcolepsy. Narcolepsy is a disorder characterized by brief attacks of deep sleeps.

2.      To curb the appetite in overweight persons.

3.      To relieve mild depression such as that accompanying grief, senility, menopause and convulsions.

4.      Use as stimulant.

In a pure state, amphetamine is a colorless, volatile liquid with a strong odor and burning state.

Administration:       Injection, oral in the form of tablet or capsule

Most common amphetamine stimulant

1.      Benzidine
2.      Dexedrine
3.      Methedrine

When taken occasionally, the effects on the person are:

1.      Exhiliration
2.      Peppiness
3.      Increase capacity for thinking

Often called “pep pills” or “jolly beavers,” when one exceeds the prescribed doses, the drug is supposed to be abused. Over dosages produce the following effects:

1.      Excitability
2.      Unclear or rapid speech
3.      Restlessness
4.      Tremors of the hand
5.      Dilated pupil
6.      Sleeplessness
7.      Profused perspiration

Hearing or visual hallucination or both may be noted especially when excessive daily doses have been taken for a long time.

Most severe complication of excessive use of amphetamine is psychoses, usually of the paranoid type. Amphetamine does not react to yield crystal on precipitate with Wagner, Mayer, Marme or picric acid reagent.

Amphetamine base and benzidine sulfate each give color reaction with various alkaloidal reagents. Place a small aliquot portion of residue into various grooves of a spot plate. Add to each groove one of the following reagents and note color produced.
                                                            Salt                              Base

1.      Sulfuric acid                          red brown                  green yellow
2.      Mandeline reagent               brick red
3.      Sulfuric acid plus
Vanillin                      brown red
4.      Froede reagent                     red
5.      Marquis reagent                   orange                        red brown


******  LYSERGIC ACID DIETHYLAMIDE (LSD–25 DELYSID)  *****

Synthesized by Stoll and Hoffman from the basic radical or ergot alkaloids. Hallucinogenic properties were discovered when they accidentally inhaled the powder.

Toxic dose I.V. LD50 for rat is 65 mg/ kg

            – toxic dose in human has not been determined
            – symptoms can be seen after ingesting 20 mg.
            – a dose of 1500 ug has been tolerated without fatality

Symptoms and actions:

1.      Hallucination of form, color, time and space are produced.

2.      Often with depersonalization of the subject so that he seems to observing himself from a distance.

3.      Restlessness, vertigo, nausea and vomiting.

4.      Increase body temperature

5.      Vascular hypotension

6.      Increased rate of breathing and parasthesias

7.      Atropine like effects like dilatation of the pupils and dryness of the mouth

8.      LDS is a potent antagonist of 5–hydroxytryptamine.


Distribution in brain

1.      In the brain of monkey, it is localized in area concerned with peripheral integration and emotional reaction.

2.      Concentration is low in the neocortex which controls simple perception, locomotion and reasoning.

3.      Concentration is three times as high in the hypothalamus, limbic cortex and in the auditory and visual reflex centers.


Fate and excretion

The drug is oxidized to 2–oxyl–LSD in the liver and excreted in the bile. Very little is found in the urine.


******  MARIJUANA (CANNABIS SATIVA)  ******

Derived from the plant, “Hemp.” Hemp originated in the Himalayan Mountains of Asia was used by the Chinese in the manufacture of ropes and textiles.

The flowering tops of the female plant when carefully cultivated yield a highly potent intoxicating resin. The male plant does not secrete any resin. The male plant does not secrete any resin and is the source of raw materials for the manufacture of linseed oil substitutes and of fibers for the textiles and ropes.

Tetrahydrocannabinol (THC) is the chemical responsible for the intoxicating properties of hemp.

Symptoms of toxicity

1.      Acts as descending depressants with generalized depression of the reticular formation and the primary pathways.

2.      Dissociation and disorientation of personality are more frequent

3.      Euphoria, emotional excitement, uncontrolled laughter, hallucination and illusion

4.      Great distortion of the sense of time and space.

5.      Increase sensitivity to sound and feeling.

6.      Acts of violence due to ideas of persecution are common.

7.      Amorous tendencies are described.


Duration of poisoning

Because THC is lipid soluble, it has tendency to accumulate in body fat where it has a half–life of 7–8 days. Chronic use at intervals less than the half–life results in large amounts of THC being stored in fatty tissue. THC may remain detectable in urine for several days to 1 week after a single exposure. In a heavy long term user, THC that has accumulated in fatty tissue is gradually released into the circulation and it may remain detectable for 21–30 days after the last dose.


******  PHENCYCLIDINE (PCP)  ******

It causes hallucination but may also act as both CNS stimulant and depressant. PCP was originally developed as a short–acting analgesic for humans and later used as a veterinary anesthetic.

A person who has taken PCP may exhibit depressant, stimulant or hallucinogenic patterns depending on dosage and route of administration. At low doses, the user may experience euphoria. Overdoses may cause the user to have a sense of superhuman strength and may also lead to coma.

Other symptoms of PCP overdose include generalized muscle rigidity, seizure, tachycardia and hypertension.


*******  OPIATES  ******

Symptoms of opiate use include CNS depression, shallow respirations with a slow respiratory rate, pin point pupils and hypothermia. The opiates are one of the minority of drugs or drug groups that have a specific antidote.

Patients who are suspected of ingesting an overdose of any of the opiates are treated with naloxone (Narcan). Naloxone is a specific opiate antagonist that reverses CNS depression within 1 to 3 minutes. Because it has no significant side effects, naloxone may be used both diagnostically and therapeutically. Naloxone is given to a patient who exhibit signs of narcotic overdose before results of a drug screen known. If the patient’s symptom improves, then one of the opiates is assumed to be the cause; if there is no improvement, opiates can be ruled out. Naloxone can also be used in treating patient with propoxylene toxicity.


CONCEPT OF A PSEUDOCHOLINESTERASE ACTIVITY

Pseudocholinesterase (ChE) activity in serum probably represents a group of 11 or more enzymes that are capable of hydrolyzing several choline esters other than acetylcholine (e.g., benzoxylcholine, butyrylthiocholine) and are reduced in activity after pesticide exposure. The physiologic role of these enzymes is not known, but their activities in serum are decreased after acute exposure to organophosphate and carbamate pesticides. Activities are also decreased in liver disease, chronic alcoholism and malnutrition and in patients with inherited forms of ChE that have decreased activity.

Methods for measurement of serum ChE activity are usually based on hydrolysis of synthetic substrate, a thiocholine ester, to release thiocholine, which then reacts with a color reagent to produce a color product that absorbs at 405 – 410 nm. This method has been automated for the DuPont ACA and several manual methods are available in kit forms.

Serum ChE activity may be lowered by exposure to levels of pesticides less than those necessary to produce clinical symptoms and may thus be considered a sensitive indicator of pesticide exposure. ChE may be decreased within 24 hours after exposure and decreases may persist for several weeks.

Laboratory diagnosis of poisoning

1.      Screening methods

a.      Spot test and color reactions – reagents are added to an aliquot of the specimen and a colored complex is formed in the presence of a particular drug.

(1)   Used for

Acetaminophen
Imipramine
Salicylates
Phenothiazines

(2)   Advantages

No sample pre–treatment
Rapid and inexpensive
Require little technical expertise

(3)   Disadvantages

Less sensitive and specific

b.     Immunoassays – a drug present in a patient specimen competes with a labeled drug for a limited number of binding sites on antibodies that are specific for the drug being measured.

(1)   Radioimmunoassay
(2)   Enzyme–multiplied immunoassay technique (EMIT)
(3)   Fluorescence polarization immunoassay (FPIA)

Advantages

(1)   RIA is the most sensitive but require long incubation period and are not suitable for drug screening in emergency situation

(2)   EMIT and FPIA requires no sample pre–treatment, are sensitive in the microgram to nanogram per milliliter range. Provide the rapid turn around time suitable for emergency situation, and have been adapted for use on automated instruments.

Disadvantages

(1)   Each immunoassay test is specific for one drug or drug group and test are not available for every drug.

(2)   Some immunoassays cross–react with other structurally similar drugs or drug metabolite.

c.       Thin layer Chromatography

2.      Confirmatory methods

a.      Gas Liquid Chromatography
b.      High Performance Liquid Chromatography (HPLC)

c.       Gas Chromatography–Mass Spectrophotometry 




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